Breast cancer is a major health problem here in the US and globally and thus, there is an urgent need to identify and develop novel markers for breast cancer that would facilitate early diagnosis and response to therapy and also serve as targets to develop novel therapeutic approaches. Mitochondria are involved in various cellular processes including control of apoptosis and mitochondrial dysfunction has also been associated with breast cancer. This application proposes to characterize a novel DNA damage-regulated mitochondrial anti-apoptotic protein CHCM1 (Coiled coil Helix Cristae Morphology 1) in human breast cancer. Our preliminary results indicate that CHCM1 expression is increased in human breast cancers and its knockdown sensitizes breast cancer cells to apoptosis induced by DNA damage inducing anticancer drugs. Our results also indicate that CHCM1 is linked to controlling mitochondrial cristae structures and that it interacts with mitofilin, which is another mitochondrial protein. Our hypothesis is that CHCM1 is a novel anti-apoptotic molecule that plays an important role in breast cancer cell survival and tumorigenesis. We also hypothesize that CHCM1 can potentially serve as a valuable novel marker for breast cancer and a molecular target to develop newer cancer therapeutic approaches. It is also our hypothesis that CHCM1 interacts with mitofilin to control the structural integrity of mitochondrial cristae and regulate cristae remodeling. We are proposing three specific aims to test these hypotheses. Specific aim 1 is to investigate CHCM1 expression in primary breast cancer samples and matching normal tissues. Specific aim 2 is to investigate the role of CHCM1 in in vivo breast cancer growth using a mouse xenograft model. Specific aim 3 involves structural functional characterization of CHCM1. The outcome of the proposed studies, if successful, will provide valuable information about the role of CHCM1 in breast cancer development and progression and facilitate the development of CHCM1 as a novel marker for breast cancer and a target for newer therapeutic approaches. The outcome will also provide valuable insights into the molecular mechanisms involved in regulation of mitochondrial cristae structure and remodeling particularly as they relate to pathobiology of breast cancer. PUBLIC HEALTH RELEVANCE: The outcome of the proposed studies will provide valuable information about the role of CHCM1 in breast cancer development and progression and facilitate the development of CHCM1 as a novel marker for breast cancer and a target to develop newer therapeutic approaches. The outcome will also provide valuable insights into the molecular mechanisms involved in regulation of mitochondrial cristae structure and remodeling particularly as they relate to pathobiology of breast cancer.